Brain Uptake of Nonsteroidal Anti-Inflammatory Drugs: Ibuprofen, Flurbiprofen, and Indomethacin

Parepally, Jagan; Mandula, Haritha; Smith, Quentin R.

doi:10.1007/s11095-006-9905-5

Cited by 163 publications

(117 citation statements)

References 38 publications

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“…Ibuprofen is an NSAID that has been demonstrated to readily cross the blood-brain barrier (34) and exert memory-enhancing effects (29). The present study investigated the neuroprotective effects of ibuprofen (100 mg/kg/day) in an AlCl 3 -induced mouse model of neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Ibuprofen targets neuronal pentraxins expresion and improves cognitive function in mouse model of AlCl3-induced neurotoxicity

Jamil

Mahboob

Ahmed

2015

Experimental and Therapeutic Medicine

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Abstract. Aluminum is known to exert neurotoxic effects associated with various neurodegenerative disorders, including Alzheimer's disease (AD). Ibuprofen is a well-known non-steroidal anti-inflammatory drug, which has demonstrated potential efficacy in the treatment of numerous inflammatory and neurodegenerative disorders, including AD. The present study aimed to investigate the protective effects of ibuprofen on cognitive function, and the expression levels of neuronal pentraxins (NPs) and interleukin (IL)-1β in an aluminum chloride (AlCl 3 )-induced mouse model of neurotoxicity. The effects of ibuprofen (100 mg/kg/day for 12 days) on learning and memory were evaluated in the AlCl 3 -induced neurotoxic mice using a Morris water maze and open field tests. In addition, ibuprofen was assessed for its effects on the expression levels of NPs and IL-1β in the hippocampus, cortex and amygdala of the brain. Treatment of the AlCl 3 -treated mice with ibuprofen decreased anxiety levels (6.90±0.34 min) compared with the AlCl 3 -treated group (1.80±0.29 min), as indicated by the time spent in the central area in an open field test. Furthermore, the expression levels of NP1 (1.32±0.47) and IL-1β (0.99±0.21) were significantly decreased in the hippocampus of mice following ibuprofen treatment, as compared with the AlCl 3 -treated mice (8.62±1.54 and 7.47±0.53, respectively). In the present study, ibuprofen was able to target novel structures in order to attenuate the inflammation associated with an AlCl 3 -induced mouse model of neurotoxicity; thus suggesting that ibuprofen may be considered a potential therapeutic option for the treatment of neurodegenerative diseases, including AD.

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Section: Discussionmentioning

confidence: 99%

Ibuprofen targets neuronal pentraxins expresion and improves cognitive function in mouse model of AlCl3-induced neurotoxicity

Jamil

Mahboob

Ahmed

2015

Experimental and Therapeutic Medicine

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“…Because urinary PGE2 may be mostly derived from interstitial cell production, 79 the lack of decreased urinary PGE2 observed in COX-inhibitortreated rats 81 may reflect an inability of the drug to reach these cells in the papilla, where renal blood flow is relatively low. Furthermore, the three nonsteroidal antiinflammatory drugs used in the study can cross the blood-brain barrier 83,84 ; thus, whether their effects are restricted to the CD or due to effects on the hypothalamus is an issue for speculation. Plasma VP levels measured in parallel could help to elucidate this.…”

Section: A Role For Renal Prostanoids In Physiologic Water Excretionmentioning

confidence: 99%

Is There a Role for PGE2 in Urinary Concentration?

Olesen

Fenton

2013

Journal of the American Society of Nephrology

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Prostanoids are prominent, yet complex, components in the maintenance of body water homeostasis. Recent functional and molecular studies have revealed that the local lipid mediator PGE2 is involved both in water excretion and absorption. The biologic actions of PGE2 are exerted through four different G-protein-coupled receptors; designated EP1-4, which couple to separate intracellular signaling pathways. Here, we discuss new developments in our understanding of the actions of PGE2 that have been uncovered utilizing receptor specific agonists and antagonists, EP receptor and PG synthase knockout mice, polyuric animal models, and the new understanding of the molecular regulation of collecting duct water permeability. The role of PGE2 in urinary concentration comprises a variety of mechanisms, which are not fully understood and likely depend on which receptor is activated under a particular physiologic condition. EP3 and microsomal PG synthase type 1 play a role in decreasing collecting duct water permeability and increasing water excretion, whereas EP2 and EP4 can bypass vasopressin signaling and increase water reabsorption through two different intracellular signaling pathways. PGE2 has an intricate role in urinary concentration, and we now suggest how targeting specific prostanoid receptor signaling pathways could be exploited for the treatment of disorders in water balance. The neurohypophyseal hormone, vasopressin (VP), is a major regulator of renal water excretion, predominantly through the seven trans-membrane receptor (7TMR) V2R. It binds to Gas, inducing the cAMP second messenger system, resulting in increased NaCl absorption by the thick ascending limb and increased urea transport in the inner medullary collecting ducts (IMCDs). [1][2][3] In addition, VP induces accumulation of the water channel aquaporin-2 (AQP2) in the rate-limiting apical plasma membrane of collecting duct (CD) principal cells, 4 a process that involves a diverse range of post-translational modifications including phosphorylation of AQP2. 5 Thus, VP increases the osmotic gradient for water transport and the water permeability (Pf) of the CD simultaneously.In addition to systemic hormones, local regulatory factors play a role in the CD, of which PGE2 (Figure 1) is the focus of this review. 6-9 PGE2 has a diverse range of biologic actions elicited by four different 7TMRs. The renal localization of EP receptors and intracellular signaling pathways are diverse (Table 1). Here, we propose that urinary concentration does not rely exclusively on fluctuations in plasma VP concentrations, but that the locally derived lipid mediator, PGE2, plays an important role in regulating water excretion. PGE2 IN THE MODULATION OF URINARY CONCENTRATING MECHANISMSThe ability of PGE2 to modulate the effects of VP in the CD has been described in a range of experimental studies and discussed in previous reviews. [36][37][38][39] The present focus is on understanding the mechanisms for this effect, and on recent in vivo studies elucidating the role of P...

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“…Preclinical studies had shown that tarenflurbil did not penetrate blood-brain barrier (BBB) satisfactorily in rodents, with a 1.3% ratio of cerebrospinal fluid (CSF) to plasma and negligible tarenflurbil level measured in the brain ($2 mM) (Peretto et al, 2005;Kukar et al, 2007). In addition, both the high affinity to serum albumin and the active efflux transport restricted the passive diffusion of FLU to the brain (Parepally et al, 2006). The limited BBB penetration of tarenflurbil makes large dosage a necessity thus increased the risk of adverse effects.…”

Section: Introductionmentioning

confidence: 99%

Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations

Zheng

Xiao

et al. 2014

Drug Delivery

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Tarenflurbil (R-flurbiprofen) was acknowledged as a promising candidate in Alzheimer's disease (AD) therapy. However, the Phase III study of tarenflurbil was extremely restricted by its poor delivery efficiency to the brain. To tackle this problem, the novel carriers for tarenflurbil, racemic flurbiprofen (FLU) derivatives (FLU-D1 and FLU-D2) modified by N,N-dimethylethanolaminerelated structures were synthesized and characterized. These derivatives showed good safety level in vitro and they possessed much higher cellular uptake efficiency in brain endothelial cells than FLU did. More importantly, the uptake experiments suggested that they were internalized via active transport mechanisms. Biodistribution studies in rats also illustrated a remarkably enhanced accumulation of these derivatives in the brain. FLU-D2, the ester linkage form of these derivatives, achieved a higher brain-targeting efficiency. Its C max and AUC 0-t were enhanced by 12.09-fold and 4.61-fold, respectively compared with those of FLU. Additionally, it could be hydrolyzed by esterase in the brain to release the parent FLU, which might facilitate its therapeutic effect. These in vitro and in vivo results highlighted the improvement of the braintargeted delivery of FLU by making use of N,N-dimethylethanolamine ligand, with which an active transport mechanism was involved.

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Brain Uptake of Nonsteroidal Anti-Inflammatory Drugs: Ibuprofen, Flurbiprofen, and Indomethacin

Abstract: Free ibuprofen, flurbiprofen, and indomethacin rapidly cross the BBB, with ibuprofen exhibiting a saturable component of transport. Plasma protein binding limits brain NSAID uptake by reducing the free fraction of NSAID in the circulation.

Cited by 163 publications

References 38 publications

Ibuprofen targets neuronal pentraxins expresion and improves cognitive function in mouse model of AlCl3-induced neurotoxicity

Ibuprofen targets neuronal pentraxins expresion and improves cognitive function in mouse model of AlCl3-induced neurotoxicity

Is There a Role for PGE2 in Urinary Concentration?

Novel flurbiprofen derivatives with improved brain delivery: synthesis, in vitro and in vivo evaluations

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